In the known processes for synthesizing antibacterial cephalosporin compounds, naturally produced cephalosporin C, or a derivative thereof, such as 7-aminocephalosporanic acid (7-ACA), is often used as the starting material. These well-known starting materials can be characterized as having an acetyloxymethyl substituent in the 3-position of the molecule.
In order to obtain synthetic cephalosporins having desirable antibacterial Properties. it is often needed to have an appropriate substituent at the 3'-methyl group of cephalosporins. Among them is the substitution of a different acyloxy group. To achieve this, the starting material (e.g., 7-ACA) is deacetylated with aqueous sodium hydroxide or acetylesterase to yield a 3-hydroxymethyl derivative which is then subjected to acylation with a suitable acyl group.
Typically, the acylation is performed by reacting an acid chloride, for example, with the 3-hydroxymethyl substituent in the presence of a base using the Schotten-Baumann technique. Alternatively, an acid anhydride may be substituted for the acid chloride, although the acid chloride is generally preferred. The base may be sodium hYdroxide or pyridine, for example, depending on the solvent employed. The base neutralizes the hydrogen chloride that would otherwise be liberated, and may also help to catalyze the reaction.
In the above described technique, unwanted side reactions may occur which have the effect of decreasing yields and/or complicating the synthesis. One such unwanted side reaction is the so-called .DELTA..sup.3 to .DELTA..sup.2 bond migration (which generally inactivates or at least reduces the antibacterial activity of the resulting cephalosporin compound). An example of a 3-acetyloxymethyl .DELTA..sup.2 -cephalosporin compound would be a compound of the formula ##STR3##
Another unwanted side reaction is known as lactonization--in which the 2-carboxylic acid group of the cephalosporin molecule reacts with the 3-hydroxymethyl substituent to form a lactone. Yet another problem which is encountered in the known synthesis techniques is that a large excess of the acid chloride or of the acid anhydride is often required, particularly when the reaction is carried out in an aqueous medium.
The above-noted problems have long been known in the art. However, little progress has heretofore been made towards a satisfactory solution thereto.
For example, Van Heynigen, J. Med. Chem., Vol. 8, pp 22-25 (1965) describes the preparation of 3-acyloxymethyl derivatives from naturally produced cephalosporin C. First the acetyl group of cephalosporin C is removed by enzymatic hydrolysis using citrus acetylesterase (the orange peel enzyme). The resulting 3-hydroxymethyl derivative is then acylated with either aroyl halides or aliphatic acid chlorides using the Schotten-Baumann technique employing sodium hydroxide in aqueous acetone. The pH of the reaction mixture had to be kept high to get the best yield (to avoid lactone formation). However, the aliphatic acid chlorides reacted preferentially with water and no acylation took Place. Even with the aroYl halides it was found that a large excess of this reagent was necessary to obtain even moderate yields.
Kukolja, S., J. Med. Chem., Vol. 13, pp 1114-1117 (1970), describes a Process using a 3-hydroxymethyl .DELTA..sup.2 -cephalosporin as the starting material (which is reportedly less Prone to lactonization than the corresponding .DELTA..sup.3 compound). It is acylated using aliphatic acid anhydride in pyridine. The resulting 3-acyloxymethyl .DELTA..sup.2 -cephalosporin is then subjected to an oxidative-reductive process to isomerize the .DELTA..sup.2 - double bond into the .DELTA..sup.3 position.
To reduce the lactonization side reaction, the following examples describe known acylation procedures which involve the use of the ester of cephalosporanic acids. In each case, the protecting group of the acid eventually has to be removed to yield the biologically active form.
T. Takaya, et. al., The J. of Antiobiotics, Vol. 34, pp.1300-1310 (1981) describes the acylation of the 3-hydroxymethyl function of the ester of cephemoic acids with aliphatic acid chlorides or aroyl chlorides in the presence of triethylamine. A mixture of .DELTA..sup.2 - and .DELTA..sup.3 -acyloxymethylcephems were obtained in these reactions. The desired .DELTA..sup.3 -isomers were prepared from the above mixture by utilizing the oxidative-reductive process for isomerization of the double bond.
U.S. Pat. No. 3,532,694 describes techniques for converting the 3-hydroxymethyl group of cephemoic acids to a 3-acyloxy grouP. As described therein, the carboxylic acid group of the cephemoic acid is first protected with an aralkyl group, e.g. benzyl. The acylation of the 3-hydroxymethyl group is then performed using acid chloride, acid anhydride or mixed acid anhydrides in the presence of an organic base, e.g. pyridine, in an inert anhydrous solvent. It is noted therein that acid chlorides are Preferred because the anhydrides tend to give lower yields due to lactone formation. It is also noted therein that .DELTA..sup.3 to .DELTA..sup.2 bond migration is a problem encountered with the described techniques, necessitating that the acylation reaction be effected as rapidly as possible.
EP 265,185 describes similar methods for acylating the 3-hydroxymethyl group in .DELTA..sup.3 -cephalosporin compounds by reacting same with an acid halide. The reaction is carried out in a nonaqueous medium, preferably in a chlorinated hydrocarbon solvent such as dichloromethane. Particular examples. wherein pyridine is employed as the base are also disclosed. Although EP 265,185 does not discuss the problems noted above, it appears from the synthesis examples which are described therein that the same problem of low yield was encountered.
Thus, in summary, the known acylation methods have a number of disadvantages, including the following:
(1).DELTA..sup.3 to .DELTA..sup.2 bond migration necessitates further processing of the acyloxymethyl cephalosporin compounds using the oxidative-reductive process to restore the .DELTA..sup.3 bond;
(2) lactonization reduces yields;
(3) the need to carefully control reaction conditions to reduce .DELTA..sup.3 to .DELTA..sup.2 bond migration and lactonization makes the known acylation methods difficult to perform; and
(4) a large excess of the acid halide or acid anhydride is generally required.